Current and future strategies aiming at reducing catecholamine exposure in septic shock

Norepinephrine is the first-line vasopressor in septic shock, yet prolonged catecholamine exposure is associated with adverse effects that have prompted growing interest in catecholamine-sparing strategies. This review highlights current evidence on the rationale for catecholamine use, the burden of sustained adrenergic exposure, and current and emerging sparing strategies. Early norepinephrine initiation, including via peripheral access, shortens hypotension duration and reduces fluid requirements. However, catecholamine exposure can carry dose-dependent cardiac, metabolic, and immunological consequences. Perfusion-guided strategies, including individualization of blood pressure targets and titration of vasopressor use based on capillary refill time, represent the cornerstone of reduction of catecholamines. Among alternative non-adrenergic vasopressors, vasopressin reduces catecholamine exposure and the risk of atrial fibrillation, with potential renal benefits. Angiotensin II represents an option in catecholamine-refractory shock, with post-hoc evidence suggesting benefit in patients with acute kidney injury or elevated renin concentrations. Inhibition of circulating dipeptidyl peptidase 3, which degrades angiotensin II, is an emerging therapeutic strategy. Corticosteroids restore vasopressor sensitivity and accelerate catecholamine weaning. Short-acting β1-blockers have shown hemodynamic promise but inconsistent outcomes, underscoring the need for better patient selection. Methylene blue, targeting the vasodilatory nitric oxide pathway, represents another strategy. Finally, emerging immunomodulatory approaches, including extracellular histone neutralization and polymyxin B hemoperfusion in endotoxin phenotypes, aim to attenuate the dysregulated host response driving vasopressor dependency. A personalized and multimodal approach, including perfusion-guided targets, non-adrenergic vasopressors, and phenotype-based patient selection, represents the most promising strategy to reduce potential consequences of adrenergic burden while maintaining tissue perfusion.